To continue and expand ongoing investigations of normal and abnormal human hemoglobins (Hb) and other hemoglobinopathies following four specific directions. 1. Attempts will be made to refine and improve (HPLC) methodology useful for a. isolation, quantitation and characterization of abnormal Hbs; b. identification of Gamma chain variants; c. separation of the Gamma chains of Hb F so that even the Hb F of the normal adult can be evaluated. 2. Characterization of the chemical and functional properties of human Hb variant, particularly those being abnormal in the Gamma chains because new micro methodology will greatly facilitate such studies. 3. Characterization of the Gamma chain composition (GGamma, AGammaI, AGammaT) of the Hb F from adults, newborn babies from various countries, and from patients with different forms of Beta, DeltaBeta, Gamma thalassemia, and HPFH. In most instances, these results will be correlated with gene mapping data to allow an insight into the regulation of the synthesis of the Gamma chains at the gene level. 4. Continuation and expansion of DNA analytical studies to evaluate genetic abnormalities in the many patients with hemoglobinopathies who have been (or will be) studied in the P.I.'s laboratories. The DNA from different patients with Beta- or DeltaBeta-thalassemia, newborns with different GGamma to AGamma ratios, patients with different forms of HPFH, a.o., will be investigated. The studies will include restriction endonuclease gene mapping and haplotyping, while cloning and sequencing will be applied to the DNA of patients with selected abnormalities. It is anticipated that these studies will help define in detail normal and abnormal mechanisms of Hb synthesis in disease states, and will be useful for an evaluation of the activation and/or deactivation of structural genes, i.e. the high GGamma -- low GGamma switch, particularly.